Establishment and Application of a Predictive Model for Gefitinib-Induced Severe Rash Based on Pharmacometabolomic Profiling and Polymorphisms of Transporters in Non-Small Cell Lung Cancer

Background: Gefitinib-induced rash is a sign of favorable outcomes for patients with non-small cell lung cancer (NSCLC). However, whether patients with more severe rash, the more survival benefits obtained from gefitinib is still unknown, and as for the severe rash a risk factor prediction model is needed. Method: A total of 346 patients were enrolled in this study. Gefitinib/metabolites and 9 gene polymorphisms, were determined by pharmacometabolomic and pharmacogenomics methods in an exploratory cohort. External cohort patients were enrolled to validate this model. Findings: The survival for patients with rash were significantly higher than patients without rash (p=0.0002, p= 0.0089)，but no difference was found between grade 1/2 or grade 3/4. Only the concentration of gefitinib, but not its metabolites, was associated with severe rash, and the cutoff value of gefitinib was 204.6 ng/mL conducted by ROC curve (AUC=0.685). A predictive model for severe rash was established: gefitinib concentration (OR = 11.523, 95%CI=2.898-64.016, p = 0.0016), SLC22A8 rs4149179(CT vs CC, OR = 3.156, 95%CI = 0.958-11.164, p = 0.0629), SLC22A1 rs4709400(CG vs CC, OR = 10.267, 95%CI = 2.067-72.465, p = 0.0087; GG vs CC, OR=5.103, 95%CI=1.032-33.938, p=0.061). This model was confirmed in validation cohort with an excellent predictive ability (AUC = 0.749, 95%CI = 0.710-0.951). Interpretation: Our finding demonstrated that patients developed any grade rash predicted improved survival, the gefitinib concentration and polymorphisms of SLC22A8 and SLC22A1 were recommended to manage severe rash. However, our model would require further validation in a biomarker-led trial. Trial Registration: This study was registered at ClinicalTrials.gov (NCT01994057). Funding Statement: This study was funded by the National Natural Science Foundation of China (Grant Nos. 81730103, 81320108027, 81573507, 81473283, 81173131 and 81973398), The National Key Research and Development Program (Grant Nos. 2017YFC0909303 and 2016YFC0905001), Guangdong Provincial Key Laboratory of Construction Foundation (Grant No. 2017B030314030), Science and Technology Program of Guangzhou（201607020031）, National Engineering and Technology Research Center for New drug Druggability Evaluation (Seed Program of Guangdong Province (No. 2017B090903004) and the 111 project (Grant: B16047). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The study was approved by Human Ethics of Sun Yat-sen University Cancer Center (B2013-038-1) and conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice Guidelines of the International Conference on Harmonization.